The present invention is directed toward a composition that inhibits certain enzymes of the coagulation cascade. More particularly, the invention relates to a composition comprising a compound isolated from Dysidea sponges that may be used for the prevention and treatment of thrombotic conditions such as coronary artery and cerebrovascular disease.
Hemorrhage, intravascular thrombosis, and embolism are common clinical manifestations of many diseases [see R. I. Handin in Harrison""s Principles of Internal Medicine (J. D. Wilson, et al. eds., 12th ed. 1991) New York, McGraw-Hill Book Co., pp. 348-351]. The normal hemostatic system limits blood loss by precisely regulated interactions between components of the vessel wall, circulating blood platelets, and plasma proteins. Unregulated activation of the of the hemostatic system, however, may cause thrombosis, which can reduce blood flow to critical organs like the brain and myocardium. Physiological systems control the fluidity of blood in mammals [see P. W. Majerus, et al. in Goodman and Gilman""s The Pharmacological Basis of Therapeutics (J. G. Hardman and L. E. Limbird, eds., 9th ed. 1996) New York, McGraw-Hill Book Co., pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet quickly be able to undergo hemostasis. Hemostasis, or clotting, begins when platelets first adhere to macromolecules in subendothelian regions of injured and/or damaged blood vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.
Plasma coagulation factors, also referred to as protease zymogens, include factors II, V, VII, VIII, IX, X, XI, and XII. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called xe2x80x9ccoagulation cascadexe2x80x9d or chain reaction. Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with factor Va converts prothrombin (II) to thrombin (IIa) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion of coagulation factor VII to VIIa by Xa. Factor VIIa, a plasma protease, is exposed to, and combines with its essential cofactor tissue factor (TF) which resides constitutively beneath the endothelium. The factor VIIa/TF complex that forms proteolytically activates its substrates, factors IX and X, triggering a cascade of reactions that lead to the generation of thrombin and a fibrin clot as described above. The many different coagulation factors, coupled with the two distinct coagulation pathways, have led researchers to search for compounds that efficaciously and selectively control the clotting process. In addition, these compounds may provide a better understanding of the pathways involved in the coagulation process.
While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals, clotting can also lead to disease states. A pathological process called thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery. When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
Although direct thrombin inhibitors of various structural classes have been identified recently (Tapparelli et al., Trends in Pharmacological Sciences 14:366-376 (1993); Claeson, Blood Coagulation and Fibrinolysis 5:411-436 (1994); Lefkovits and Topol, Circulation 90(3):1522-1536 (1994), to date only three classes of compounds (heparins, low-molecular weight heparins and coumarins, such as warfarin) have been used in anticoagulant therapy. Each class has severe limitations and liabilities (Weitz and Hirsh, Journal of Laboratory Clinical Medicine 122:364-373 (1993); Raj et al., The American Journal of the Medical Sciences 307(2):128 (1994)). All three classes indirectly inhibit thrombin. Heparin and low-molecular weight heparins augment anti-thrombin III and/or heparin cofactor II inhibition of thrombin, whereas coumarins inhibit vitamin K-dependent post-translational modifications. Close monitoring and titration of therapeutic doses is required when employing these agents due to patient variability. Hemorrhagic complications due to bleeding are an encountered side effect. In fact, bleeding remains as the most common side effect of long term oral anticoagulant therapy. Lack of activity in arterial thrombosis in the case of heparin is due to its inability to inhibit clot bound thrombin. Lack of oral activity in the case of heparins and low-molecular weight heparins preclude their use for chronic administration.
One aspect of the present invention provides a compound which may be isolated from Dysidea sp. sponges that may be beneficially employed in anticoagulant therapy. The compound corresponds to structure (1): 
or a pharmaceutically acceptable salt, prodrug, tautomer or isomer thereof.
In yet another aspect of the present invention is provided a pharmaceutical composition comprising a compound corresponding to structure (1) or a pharmaceutically acceptable salt, prodrug, tautomer or isomer thereof and at least one pharmaceutically acceptable carrier.
In a further aspect of the invention is provided an extract from a Dysidea sponge comprising a compound having structure (1) or a pharmaceutically acceptable salt, prodrug, tautomer or isomer thereof.
In still another aspect of the present invention is provided methods for preventing and treating thrombotic conditions, such as coronary artery disease, cerebrovascular disease, and other coagulation related disorders by administering a compound having structure (1) or a pharmaceutically acceptable salt, prodrug, tautomer or isomer thereof to a subject.
Other features and aspects of the present invention will be in part apparent to those skilled in the art and in part pointed out in the detailed description provided below.